Obstructive sleep apnea (OSA) is a common disorder characterized by upper airway obstruction and alveolar hypoventilation during sleep. Current evidence suggests that upper airway collapse is due to alterations in structural properties and/or a disturbance in neuromuscular control. However, their relative contribution to OSA pathogenesis is unknown. In this application, strong preliminary data is presented to suggest that sleep apnea is characterized by a fundamental defect in upper airway neuromuscular control. Our major hypothesis is that sleep apnea is associated with selective deficits in compensatory upper airway neuromuscular responses during sleep. In three specific aims, we will probe specific mechanisms (sleep state, CO2 chemoreflexes, leptiri) that modulate upper airway neuromuscular responses and establish the mechanisms for observed disturbances in upper airway neuromuscular control. Utilizing an innovative, physiologic challenge to experimentally induce upper airway obstruction, we will examine the effects of potent state-dependent, chemoreflex, and neurohumoral factors on neuromuscular responses. Complementary training and mentorship will ensure that the principal investigator gain in-depth exposure to clinical research design and to rigorous biostatistical methods that are required to establish himself as a career academician and clinical investigator in the sleep disordered breathing field. Completion of his research plan and Ph.D. training in Clinical Investigation will lay the groundwork for mechanistic interventional studies elucidating the role of neurohumoral and heritable factors on the pathogenesis of sleep apnea. Completion of the proposed research and doctoral degree, and the development of new knowledge and skills within an outstanding supportive environment for clinical research will allow the principal investigator to develop into an individual capable of pursuing a successful career in the responsible conduct of research as an independent investigator in academic medicine. (End of Abstract)